During development, epithelial cells in many tissues acquire a polarity orthogonal to their apical-basal axis. This polarity, referred to as planar cell polarity (PCP), or tissue polarity, is essential for normal physiological function. Early studies of PCP focused on insect epithelia, and indeed, most of our mechanistic understanding of PCP derives from the ongoing use of the fruitfly, Drosophila, as a model system. However, a range of medically important developmental defects and physiological processes are under control of PCP mechanisms that appear to conserve much or all of the mechanism uncovered in flies, driving considerable interest in studying PCP both in Drosophila and in vertebrate model systems. Defects in PCP result in a range of developmental anomalies and diseases. Perhaps best characterized among these, PCP is required for the correct orientation of sensory hair cells in the organ of Corti of the inner ear, and defects result in deafness. Other PCP related developmental defects in humans and in model organisms include open neural tube defects, polycystic kidneys, and conotruncal heart defects. PCP is also believed to underlie the pathogenesis of idiopathic pulmonary hypertension and the directed migration that occurs during invasion and metastasis of malignant cells. Despite considerable progress in recent years, the molecular mechanisms of the PCP signaling modules, and the interactions between them are as yet insufficiently understood, thereby limiting the potentially substantial opportunities for therapeutic interventions for these disorders. The goal of this proposal is to apply sophisticated genetics, microscopy and biochemical/proteomic methods to the study of PCP in the fruitfly. By doing so, we expect to advance our understanding of this important mechanism, and facilitate the development of diagnostic and therapeutic tools for these PCP-based disorders.